Program Director/Principal Investigator (Last, First, Middle): Ramanathan, Murugappan Jr It is estimated that while the majority of SARS-CoV-2 infections in the ongoing coronavirus disease-2019 (COVID-19) pandemic are asymptomatic or have mild symptoms, hospitalizations and mortality largely occurs in patients with co-morbid conditions such as obesity, diabetes and COPD. Our understanding of the role of environmental exposures in modifying the response to SARS-CoV-2 is emerging and air pollution, smoking and vaping have been associated with worst outcomes of SARS-CoV-2 patients. There is a time sensitive urgent need to understand host defense mechanisms in the sinonasal epithelia which are compromised due to environmental exposures and may increase susceptibility to SARS-CoV-2 infection. This administrative supplement will forge collaboration with an expert in SARS-CoV-2 research to expand our horizon in this critical area. We will test the hypothesis of targeting a host defense pathway which is compromised in air pollution that may protect and modify the response to SARS-COV-2 respiratory infection. Through the parent R01 grant, we have demonstrated that chronic exposure to PM2.5 has an overarching role in epigenetic reprogramming. Our studies have established that transcription factor Nuclear factor erythroid-factor 2 (Nrf2) is a key activator of anti-oxidative, anti-inflammatory, and innate immune defenses. We and others have demonstrated in human biospecimens and animal models that chronic exposure to PM2.5 causes a decline in Nrf2 activity that correlates with compromised innate immune defenses. In mice deficient for Nrf2 (Nrf2-/-), viral and bacterial infection causes oxidative stress, worsened lung inflammation, acute lung injury and greater mortality compared to wildtype mice. Genetic or pharmacological activation of Nrf2 pathway can rescue these effects. Disruption of Nrf2 pathway has been shown to cause upregulation of angiotensin-converting enzyme 2 (ACE2) which is the functional receptor for SARS-CoV2 entry into airway epithelial cells. Furthermore, hypomethylation of the ACE2 gene has been demonstrated to increase ACE2 expression in immunocompromised patients. The goal for this administrative supplement (in response to NOT-AI-020-031) is to investigate the crosstalk of air pollution exposure, host defense and SARS-CoV-2 infection. If this pilot project is successful, preclinical testing of Nrf2 activators will provide proof of concept for further development a novel drug target for prevention and treatment of SARS-CoV-2 infection. The proposal will leverage expertise of our team on air pollution, respiratory diseases and an expert virologist with ongoing BSL-3 SARS-CoV-2 research. Successful completion of this project will provide proof of concept for future studies directed towards development of a novel strategy of targeting host defense for prevention and treatment of SARS-CoV-2 infection in susceptible populations.